Relevance of Abnormal KCNN1 Expression and Osmotic Hypersensitivity in Ewing Sarcoma.

Ewing sarcoma (EwS) is a rare and highly malignant bone tumor occurring mainly in childhood and adolescence. Physiologically, the bone is a central hub for Ca 2+ homeostasis, which is severely disturbed by osteolytic processes in EwS. Therefore, we aimed to investigate how ion transport proteins involved in Ca 2+ homeostasis affect EwS pathophysiology. We characterized the expression of 22 candidate genes of Ca 2+ -permeable or Ca 2+ -regulated ion channels in three EwS cell lines and found the Ca 2+ -activated K + channel K Ca 2.1 ( KCNN1 ) to be exceptionally highly expressed. We revealed that KCNN1 expression is directly regulated by the disease-driving oncoprotein EWSR1-FL1. Due to its consistent overexpression in EwS, KCNN1 mRNA could be a prognostic marker in EwS. In a large cohort of EwS patients, however, KCNN1 mRNA quantity does not correlate with clinical parameters. Several functional studies including patch clamp electrophysiology revealed no evidence for K Ca 2.1 function in EwS cells. Thus, elevated KCNN1 expression is not translated to K Ca 2.1 channel activity in EwS cells. However, we found that the low K + conductance of EwS cells renders them susceptible to hypoosmotic solutions. The absence of a relevant K + conductance in EwS thereby provides an opportunity for hypoosmotic therapy that can be exploited during tumor surgery.